How Do Physicians Approach Intravenous Alteplase Treatment in Patients with Acute Ischemic Stroke Who Are Eligible for Intravenous Alteplase and Endovascular Therapy? Insights from UNMASK-EVT

DISCUSSION

In this multidisciplinary survey, we evaluated how physicians around the world approach intravenous alteplase treatment in patients eligible for EVT and alteplase treatment and how they would like to change their treatment practice when assuming ideal conditions (ie, in the absence of any external limitations). We found slightly lower reported intravenous alteplase decision rates under assumed ideal conditions compared with decision rates under current local resources (2.7% risk difference, Table 2). This finding mostly held true within individual countries as well (Fig 1). We suspect that under ideal conditions, EVT would be more readily available and that this reduction in reported alteplase treatment rates shows physicians’ demands for a single method of reperfusion that has a high success rate. This behavior may reflect binary thinking: One solution is preferred when, in fact, the 2 treatments may be synergistic. While intravenous alteplase has been proven to be an effective treatment in acute ischemic stroke, and although recanalization rates for LVO are lower than for distal occlusions (5–10%),^9,10 concurrent administration of alteplase and the use of EVT afford the possibility of early recanalization, even in patients with LVO.¹⁰ Furthermore, medical thrombolysis may facilitate EVT¹¹ through a reduction in a thrombus-endothelial interaction, leading to more effective first-pass reperfusion and by causing thrombolysis of distal emboli (whether such emboli are iatrogenic or due to the original stroke event).^6,12 Indeed, our results show that among those physicians who changed their treatment decision when switching from current local resources to assumed ideal conditions, most of them would opt for a combined approach and add EVT to intravenous alteplase (Fig 2). This increase in EVT rates probably occurred because access to EVT is currently limited in many hospital settings.

In contrast, there are potential negative attributes of treatment with alteplase. The efficacy of both EVT and medical thrombolysis with alteplase is highly time-dependent, and difficulties in determining intravenous alteplase eligibility and initial transfer to a primary stroke center for its administration can substantially delay EVT, thereby reducing EVT efficacy and ultimately worsening patient outcome.^13⇓⇓-16 Moreover, the absolute rate of major hemorrhage is slightly higher when alteplase is used, though it is not statistically significant.^17,18 Both EVT and intravenous alteplase may cause thrombus fragmentation and distal embolization, but when alteplase is used primarily, it may convert a relatively straightforward M1 embolectomy into a more difficult procedure, involving ≥2 middle cerebral artery branch occlusions. This feature potentially increases treatment costs without improving outcomes.¹⁹ These considerations could potentially explain why ideal alteplase rates were significantly lower (both in the overall group of participants as well as among neurologists, who constituted the largest specialty subgroup) than ideal rates, despite formal evidence for alteplase treatment. The difference was statistically significant but small and of unclear clinical significance. However, depending on the results of MR CLEAN NO IV, DIRECT-MT, and SWIFT-DIRECT, this gap might grow further in the future. The specialty of interventional neuroradiology reported a significantly increased probability of dropping intravenous alteplase when switching from current local resources to assumed ideal conditions. This is likely due to treatment familiarity, but it could also potentially reflect a bias of binary thinking in treatment decision-making. The differences between current and ideal intravenous alteplase treatment rates in different countries, and particularly between North America and Europe (Fig 1), are most likely multifactorial and related to infrastructure and local policies. While the North American and European guidelines mostly agree in their alteplase and EVT treatment recommendations, local/institutional policies might differ across countries. Because neurologists were the largest group in almost all countries, physician specialty is probably not the main reason for these discrepancies. The exact reasons for the observed differences can, however, not be determined in this study and should be made subject to further research. Particularly in developing countries, many of which were not captured in this survey, access to EVT is still lacking and intravenous alteplase remains the mainstay of acute stroke therapy.

Our study has several limitations that deserve comment. The overall response rate of this survey was modest at 45.6%. Although the difference between current and ideal intravenous alteplase decision rates was statistically significant, the overall difference was small and the clinical significance of these discrepancies remains to be clarified. Enrollment was based on institutional networks and cooperations, potentially leading to a selection bias. Neurosurgeons and interventional neuroradiologists, who made up 42% of the participants, do not decide about alteplase treatment in most practice settings. We tried to design case scenarios that reflect clinical routine as realistically as possible, but a case-based survey cannot fully capture real-life decision-making. We did not obtain any information about the specific nature of external limitations that cause the resource gaps observed in our study. Furthermore, it is possible that lack of access to EVT in participants’ current local setting, as is the case in many countries that were represented in this survey, also influences their treatment decisions under assumed ideal conditions: Physicians who do not have access to EVT might not be familiar with this treatment and might, thus, not feel comfortable offering it even if they could. Last, the results of this survey are a snapshot in time, whereas clinical decision-making is a dynamic construct; it is possible, for instance, that more liberal EVT treatment practices in the future will cause further reactive changes in intravenous alteplase treatment practice. Despite its limitations, this study helps to explore how intravenous alteplase treatment in patients with acute ischemic stroke is currently approached across a broad international, multidisciplinary spectrum and provides a helpful context for the 3 ongoing randomized trials.